In the context of the global health issue caused by the growing occurrence of antimicrobial resistance (AMR), the need for novel antimicrobial agents is becoming alarming. Inorganic and organometallic complexes represent a relatively untapped source of antibiotics. Here, we report a computer-aided drug design (CADD) based on a ‘scaffold-hopping’ approach for the synthesis and antibacterial evaluation of fac-Re(I) tricarbonyl complexes bearing clotrimazole (ctz) as a monodentate ligand. The prepared molecules were selected following a pre-screening in silico analysis according to modification of the 2,2′-bipyridine (bpy) ligand in the coordination sphere of the complexes. CADD pointed to chiral 4,5-pinene and 5,6-pinene bipyridine derivatives as the most promising candidates. The corresponding complexes were synthesized, tested toward methicillin-sensitive and -resistant S. aureus strains, and the obtained results evaluated with regard to their binding affinity with a homology model of the S. aureus MurG enzyme. Overall, the title species revealed very similar minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values as those of the reference compound used as the scaffold in our approach. The obtained docking scores advocate the viability of ‘scaffold-hopping’ for de novo design, a potential strategy for more cost- and time-efficient discovery of new antibiotics.

Cancer remains one of the leading causes of death worldwide. The interest in organometallic complexes as anticancer drug candidates continues to be pivotal for many researchers. Initially underestimated for their therapeutic potentials, rhenium complexes are now slowly gaining momentum. While tricarbonyl complexes of rhenium are widely investigated, dicarbonyl derivatives of the cis-[Re(CO)₂]⁺ core remain largely unexplored. In this study, we tested in vitro a variety of rhenium dicarbonyl complexes for their activity towards three cancer cell lines (A549, MCF-7 and HCT116) and one healthy cell line (HEK293). The most lipophilic compounds showed, like the tricarbonyl species, good activity against specific cancer lines (IC₅₀ = 1.5–2.5 µM); however, the same were also toxic towards healthy cells. In order to understand these differences, we performed a reactivity study of cis-[Re(CO)₂(NN)]⁺ species (where NN = diimine) with biologically relevant functional groups (-COOH, -NH₂, -SH and aromatic nitrogen-based ligands) and compared the chemistry to what is known for the fac-[Re(CO)₃]⁺ core. Overall, we found that the rhenium dicarbonyl complexes only show good reactivity with aromatic nitrogen-based ligands. The reaction of cis-[Re(CO)₂(NN)]⁺ species with common bio-functional groups leads, rather, to the formation of bis-diimine dicarbonyl complexes (cis-[Re(CO)₂(NN)₂]⁺) as the major by-product.

Antimicrobial resistance (AMR) poses a critical global health threat by rendering existing antibiotics ineffective against infections, leading to increased mortality, prolonged illnesses, and higher healthcare costs. Developing new antibiotics is essential to combat resistant pathogens, safeguard modern medical procedures, and prevent a return to a pre-antibiotic era where common infections become untreatable. We report a series of chiral tricarbonyl rhenium(I) complexes incorporating enantiopure pinene-substituted bipyridine ligands (L#) of the general formula fac-[Re(CO)₃L#X] and fac-[Re(CO)₃L#Py]⁺ (where X = Cl or Br and Py = pyridine). These complexes were isolated as mixtures of two diastereomers, characterized by standard techniques, and evaluated for cytotoxic activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus (MRSA and MSSA). The results revealed notable antibacterial efficacy (MIC = 1.6 μM), reflected in high therapeutic indices (Ti > 10). In contrast, analogous complexes bearing non-chiral 2,2′-bipyridine ligands exhibited no activity, underscoring the critical role of chirality in modulating biological interactions at the molecular level. These findings highlight the potential of chiral Re(I) complexes as promising scaffolds for the development of more potent and selective antibacterial agents.

Herein, a library of rhenium di‐ and tricarbonyl complexes featuring various antimicrobial azoles as monodentate ligands is synthesized and characterized. Their antimicrobial activity is evaluated against both methicillin‐sensitive (MSSA) and methicillin‐resistant Staphylococcus aureus (MRSA), and selected compounds are also assessed for cytotoxicity, yielding promising therapeutic indices. Notably, the complexation of antifungal azoles to the rhenium core enhances antimicrobial efficacy, with a compound exhibiting up to a 32‐fold improvement in minimum inhibitory concentration (MIC) values relative to the parent azole. Structure–activity relationships indicate that cationic fac‐[Re(CO)₃]⁺ complexes consistently outperform their cis‐[Re(CO)₂]⁺ counterparts, and mechanistic studies suggest that active complexes disrupt bacterial membrane integrity and interfere with the electron transport chain. Complementary small‐angle X‐ray scattering and in silico analysis corroborate these findings, offering insights into the mechanism of action of this family of complexes.

Antimicrobial resistance (AMR) is a major threat to public health, causing serious issues in the successful prevention and treatment of persistent diseases. Transition metal complexes are currently evaluated for the possible development of alternative antimicrobial agents. In our ongoing efforts to identify safe and effective rhenium-based antibiotics, we have prepared a family of compounds bearing derivatives of thiazolohydrazinylidene-chroman-2,4-diones. Two compounds were identified as being active and nontoxic in vivo (zebrafish-S. aureus ATCC43300 model of infection), efficiently eradicating Methicillin-resistant Staphylococcus aureus (MRSA) infection at doses of 500 and 520 ng/mL respectively. In vitro studies indicate that, contrary to other known active rhenium complexes, the compounds do not affect peptidoglycan synthesis or compromise the integrity of the cytoplasmic membrane, but rather that bacterial membrane depolarization may play a role in their antibiotic activity.

Numerous studies have demonstrated the ability of Ru complexes to inhibit the growth of various bacterial strains, including both Gram-positive and Gram-negative bacteria. A library of (η6-p-cymene)Ru (II) and Ru (II) bis-bpy bearing thiazolhidrazinylidene-chroman-2,4-dione was synthesized, characterized and all novel complexes were evaluated for their antibacterial activity, and cytotoxicity. From this library, many compounds were identified as being active, against Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-sensitive Staphylococcus aureus (MSSA). A polypyridyl complex, 14, showed a remarkable minimum inhibitor concentration (MIC) of 3.12 µM and therapeutic index (T.I) of >32. We performed mechanism of action studies for several complexes. We could assign disruption of bacterial membrane integrity as a possible mode of action of piano stool arene species, while the mode of action of polypyridyl complexes remains elusive.